Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma
Abstract Background Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases...
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-022-00788-0 |
| _version_ | 1819260948324548608 |
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| author | You-Liang Lai Kai-Hung Wang Hsing-Pang Hsieh Wan-Ching Yen |
| author_facet | You-Liang Lai Kai-Hung Wang Hsing-Pang Hsieh Wan-Ching Yen |
| author_sort | You-Liang Lai |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC. Methods Human HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114. Results DBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group. Conclusion Our results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC. |
| first_indexed | 2024-12-23T19:34:01Z |
| format | Article |
| id | doaj.art-da5b6894f2c24f4c97694cf8c4404855 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-12-23T19:34:01Z |
| publishDate | 2022-01-01 |
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| series | Journal of Biomedical Science |
| spelling | doaj.art-da5b6894f2c24f4c97694cf8c44048552022-12-21T17:33:50ZengBMCJournal of Biomedical Science1423-01272022-01-0129111910.1186/s12929-022-00788-0Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinomaYou-Liang Lai0Kai-Hung Wang1Hsing-Pang Hsieh2Wan-Ching Yen3Institute of Biotechnology and Pharmaceutical Research, National Health Research InstitutesInstitute of Biotechnology and Pharmaceutical Research, National Health Research InstitutesInstitute of Biotechnology and Pharmaceutical Research, National Health Research InstitutesInstitute of Biotechnology and Pharmaceutical Research, National Health Research InstitutesAbstract Background Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC. Methods Human HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114. Results DBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group. Conclusion Our results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC.https://doi.org/10.1186/s12929-022-00788-0Hepatocellular carcinomaMultikinase inhibitorsAurora kinasesSorafenib resistance |
| spellingShingle | You-Liang Lai Kai-Hung Wang Hsing-Pang Hsieh Wan-Ching Yen Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma Journal of Biomedical Science Hepatocellular carcinoma Multikinase inhibitors Aurora kinases Sorafenib resistance |
| title | Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma |
| title_full | Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma |
| title_fullStr | Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma |
| title_full_unstemmed | Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma |
| title_short | Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma |
| title_sort | novel flt3 aurk multikinase inhibitor is efficacious against sorafenib refractory and sorafenib resistant hepatocellular carcinoma |
| topic | Hepatocellular carcinoma Multikinase inhibitors Aurora kinases Sorafenib resistance |
| url | https://doi.org/10.1186/s12929-022-00788-0 |
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